Although the underlying causes of glaucoma are not understood at this time, glaucoma is characterized by damage to the optic nerve, accompanied by a decrease in the normal visual field. One early warning sign of possible glaucomatous visual field loss is elevated intraocular pressure ("IOP"). In fact, glaucoma has historically been treated by medically and/or surgically lowering elevated IOP, for example, by the administration of IOP-lowering agents such as motics, sympathomimetics, beta-blockers, and carbonic anhydrase inhibitors. However, factors other than IOP may play a role in the occurrence of visual field loss. Degeneration of retinal ganglion cells may be related to ischemia or mechanical distortion of the nerve fibers as they exit through the optic nerve head or from pathological perturbations of the retina.
There has been a growing interest in retinal dysfunction as a contributor to the glaucomatous process. Retinal dysfunction, and hence pathology, may be related to ischemia or excitotoxicity. Excitotoxicity is neuronal injury due to excessive excitatory amino acid ("EAA") stimulation. In the inner retina, glutamate is the major EAA that permits the bipolar and amacrine cells to communicate with the ganglion cell. In the central nervous system, excitotoxicity results from hypoxia, ischemia, hypoglycemia or trauma. (See, for example, Beal, M. F., "Mechanisms of excitotoxicity in neurologic diseases," FASEB J., 6:3338-3344 (1992); and Choi, D. W., "Excitotoxic cell death," J. Neurobiol., 23:1261-1276 (1992).) Toxicity to the inner retina has been observed following intravitreal injection of EAAs following application of EAAs to the isolated animal retina or from exogenously applied glutamate to retinal ganglion cells in culture. See generally, Sattayasai, et al., "Morphology of quisqualate-induced neurotoxicity in the chicken retina," Invest. Ophthalmol. Vis. Sci., 28:106-117 (1987); Tung et al., "A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick", Visual Neurosci., 4:217-223 (1990); Sisk et al., "Histological changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate," Graefe's Arch. Clin. Exp. Ophthalmol., 223:250-258 (1985); Siliprandi et al., "N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina," Visual Neurosci., 8:567-573 (1992); Reif-Lehrer et al., "Effects of monosodium glutamate on chick embryo retina in culture," Invest. Ophthalmol. Vis. Sci., 14(2):114-124 (1975); Blanks, J. C., "Effects of monosodium glutamate on the isolated retina of the chick embryo as a function of age: A morphological study," Exp. Eye Res., 32:105-124 (1981); Olney et al., "The role of specific ions in glutamate neurotoxicity," Neurosci. Lett., 65:65-71 (1986); Olney et al., "The anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics," Neurosci. Lett 68:29-34 (1986); Price et al., "CNQX potently and selectively blocks kainate excitotoxicity in the chick embryo retina," Soc. Neurosci. Abst., 14:418 (1988); David et al., "Involvement of excitatory neurotransmitters in the damage produced in chick embryo retinas by anoxia and extracellular high potassium," Exp. Eye Res., 46:657-662 (1988); Caprioli et al., "Large retinal ganglion cells are more susceptible to excitotoxic and hypoxic injury than small cells" Invest. Ophthalmol. Vis. Sci., 34(Suppl):1429 (1993); Cummins et al., "Electrophysiology of cultured retinal ganglion cells to investigate basic mechanics of damage," Glaucoma Update IV, 59-65 (1991); and Sucher et al., "N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in rat retinal ganglion cells in vitro," J. Neurosci., 11(4):966-971 (1991).
EAA receptors have been characterized as metabotropic or ionotropic. Activation of a metabotropic receptor affects cellular processes via G-proteins; whereas ionotropic receptors affect the translocation of mono- and divalent cations across the cell membrane. There are at least three ionotropic receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-methyl-D-aspartate (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoic acid). These EAA receptors are differentially distributed to specific cells in the retina. (See, for example, Massey, S., "Cell types using glutamate as a neurotransmitter in the vertebrate retina," N. N. Osborne and G. J. Chader (Eds.) Progress in Retinal Research, Ch. 9, Pergammon Press: Oxford, 399-425 (1990); and Miller et al., "Excitatory amino acid receptors in the vertebrate retina," in Retinal Transmitters and Modulators: Models for the Brain, (W. W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The localization of such receptors would account for the pathologies associated with glaucoma or inner retinal ischemia. For example, death of the retinal ganglion cell has to a large part been attributed to the NMDA receptor. (See, for example, Sucher et al., "N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vitro," J. Neurosci., 11(4):966-971 (1991).). Thus, antagonists of the NMDA receptor are neuroprotective; however, not all antagonists of the diversely distributed EAA receptors are neuroprotective to the inner retina through antagonism of the NMDA receptor, Zeevalk et al., "Action of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity," Brain Res., 522:135-139 (1990)), and many of these EAA antagonists have significant CNS side-effects and are therefore not suitable for treating these degenerative diseases of the eye.